Iacobuzio-Donahue Christine A, Maitra Anirban, Olsen Mari, Lowe Anson W, van Heek N Tjarda, Rosty Christophe, Walter Kim, Sato Norihiro, Parker Antony, Ashfaq Raheela, Jaffee Elizabeth, Ryu Byungwoo, Jones Jessa, Eshleman James R, Yeo Charles J, Cameron John L, Kern Scott E, Hruban Ralph H, Brown Patrick O, Goggins Michael
Department of Pathology, The Johns Hopkins Medical Institutions, Baltimore, Maryland 21205, USA.
Am J Pathol. 2003 Apr;162(4):1151-62. doi: 10.1016/S0002-9440(10)63911-9.
Pancreatic cancer is the fifth leading cause of cancer death in the United States. We used cDNA microarrays to analyze global gene expression patterns in 14 pancreatic cancer cell lines, 17 resected infiltrating pancreatic cancer tissues, and 5 samples of normal pancreas to identify genes that are differentially expressed in pancreatic cancer. We found more than 400 cDNAs corresponding to genes that were differentially expressed in the pancreatic cancer tissues and cell lines as compared to normal pancreas. These genes that tended to be expressed at higher levels in pancreatic cancers were associated with a variety of processes, including cell-cell and cell-matrix interactions, cytoskeletal remodeling, proteolytic activity, and Ca(++) homeostasis. Two prominent clusters of genes were related to the high rates of cellular proliferation in pancreatic cancer cell lines and the host desmoplastic response in the resected pancreatic cancer tissues. Of 149 genes identified as more highly expressed in the pancreatic cancers compared with normal pancreas, 103 genes have not been previously reported in association with pancreatic cancer. The expression patterns of 14 of these highly expressed genes were validated by either immunohistochemistry or reverse transcriptase-polymerase chain reaction as being expressed in pancreatic cancer. The overexpression of one gene in particular, 14-3-3 sigma, was found to be associated with aberrant hypomethylation in the majority of pancreatic cancers analyzed. The genes and expressed sequence tags presented in this study provide clues to the pathobiology of pancreatic cancer and implicate a large number of potentially new molecular markers for the detection and treatment of pancreatic cancer.
胰腺癌是美国癌症死亡的第五大主要原因。我们使用cDNA微阵列分析了14种胰腺癌细胞系、17例切除的浸润性胰腺癌组织以及5份正常胰腺样本中的整体基因表达模式，以鉴定在胰腺癌中差异表达的基因。我们发现，与正常胰腺相比，有400多个对应于在胰腺癌组织和细胞系中差异表达基因的cDNA。这些在胰腺癌中倾向于高水平表达的基因与多种过程相关，包括细胞间和细胞与基质的相互作用、细胞骨架重塑、蛋白水解活性以及Ca(++)稳态。两个突出的基因簇与胰腺癌细胞系中的高细胞增殖率以及切除的胰腺癌组织中的宿主促结缔组织增生反应有关。在149个被鉴定为在胰腺癌中比正常胰腺表达更高的基因中，有103个基因此前尚未报道与胰腺癌相关。其中14个高表达基因的表达模式通过免疫组织化学或逆转录聚合酶链反应得到验证，表明它们在胰腺癌中表达。特别发现，一个基因14-3-3 sigma的过表达与大多数分析的胰腺癌中的异常低甲基化有关。本研究中呈现的基因和表达序列标签为胰腺癌的病理生物学提供了线索，并暗示了大量潜在的用于胰腺癌检测和治疗的新分子标记。
